The present invention relates to (2S,3R,4S)-carboxycyclopropylglycine represented by the formula (1): ##STR3## It also relates to a process for producing this compound, as well as a process for individually synthesizing four carboxycyclopropylglycine stereoisomers including those of the following formulas (1a, 1b, 1c): ##STR4##
L-glutamic acid has been considered to be one of the most probable excitatory neurotransmitters in the mammalian central nervous system. The (2S,3R,4S)-carboxycyclopropylglycine (1) of the present invention has proved to be one of the most potent excitatory amino acid agonist by activating specifically to N-methyl-D-aspartate (NMDA) type receptor which is one of the glutamate receptor sub-types in the mammalian central nervous system. This compound provides useful tools to open a road to the development of glutamic acid receptor antagonists that may have therapeutic value in epilepsy, neuronal disorders such as Huntington's charea and Parkinsonism, as well as various acute and chronic neuro-degenerative disorders.
The four stereoisomers (1, 1a, 1b, 1c) provided by the present invention are anticipated to offer important contributions for elucidation of the mechanism of L-glutamic acid receptor interaction on the basis of the correlation between the conformations of L-glutamic acid (including their analogs) and the activities thereof.
L-glutamic acid has drawn the attention of researchers as an excitatory neurotransmitter in the mammalian central nervous system and unraveling the mechanism of its agonist-receptor interaction is one of the most important subjects currently being dealt with by life science.
Since Watkins et al. succeeded in discovering L-glutamic acid agonists using L-glutamic acid related amino acids in 196I (D. R. Curtis, J. W. Phillips, J. C. Watkins; British J. Pharmacology, 16, 262-283, 1961), a number of substances analogous to L-glutamic acid have been found date that exhibit neuronal excitatory activities.
As a result of the recent active studies conducted to unravel the function of the L-glutamic acid receptor using L-glutamic acid agonists, these receptors have been classified into the following three subtypes (J. C. Watkins, R. H. Evans; Annu. Rev. Pharmacol., 21, 165-204, 198I): N-methyl-D-aspartate (NMDA), kainate (KA), and quisqualate (QA). It has been suggested that receptors cells of the individual subtypes are distributed in certain associated sites in the central nervous system while being directly related to their corresponding neuro-physiological functions [(a) D. T. Monaghan, V. R. Holets, D. W. Toy, C. W. Cotman; Nature, 306, 176-179, 1983; (b) D. T. Monaghan, D. Yao, C. W. Cotman; Brain Res., 324, 160-164, 1984; (c) H. J. Oversman, D. T. Monaghan, C. W. Cotman, J. C. Watkins; Eur. J. Pharmac., 131. 161-162, 1986]. If the relationship between L-glutamic acid agonists and their receptors were to be unravelled at the molecular level, a great contribution would be rendered to the current efforts being made to search for more patent specific antagonists, as well as to develop glutamic acid receptor blocking agents that may have clinical therapeutic value in epilepsy, movement disorders, neuronal disorders such as Hutchinson's disease and Parkinsonism, as well as various acute and chronic neurodegenerative disorders (B. Meldrum; ISI Atlas of Science, 228-232, 1987).
Such being the circumstances surrounding the efforts so far made in studying the mechanism of L-glutamic acid reception, nobody has ever succeeded in unraveling the structural relationship between L-glutamic acid agonists and L-glutamic acid which could lead to the development of effective antagonists. While it has been shown that L-glutamic acid receptors can be classified into the three subtypes, NMDA, KA and QA, the only explanation so far proposed to structurally relate these subtypes to L-glutamic acid is that the conformation of the latter would contribute to efforts to distinguish these subtypes (J. C. Watkins, H. T. Olverman; Trend in Neuroscience, 10, 265-272, 1987). It is therefore very important to characterize the correlation between the conformation of L-glutamic acid and its activity before the mechanism of L-glutamic acid receptor interaction can be unraveIled at the molecular level.
L. Fowden et al. isolated trans- and cis-carboxycyclopropyl-L-glycine (1a, 1c) from Aesculus parviflora and Blighia sapida and found that they caused undesired effects such as hypoglycemia and vomiting (L. Fowden et al.; Phytochemistry, 8, 437, 1969). Ohfune et al. reported the synthesis of a racemate of transcarboxycyclopropylglycine (1a, 1b) from dl-.beta.-acetoxyalkylglycine (Ohfune et al.; Tetrahedron Lett., 26, 83, 1985). However, the trans- and cis-carboxycyclopropyl-L-glycine (1a, 1c) are present in plants in very small amounts and the two other stereoisomers (1b, 1d) are absent. The method reported by Ohfune et al. is merely capable of yielding a racemate of 1a, 1b for the following two principal reasons: the intermediate [3,3]-sigmatropic rearrangement product, is labile and has no stereoselectivity for cyclopropanation; the diastereomers are difficult to separate. No non-native (2S,3R,4S)-carboxycyclopropylglycine (1) has been known in the art, nor any process for producing the same. Neither has any process been reported for synthesizing the four possible stereoisomers as the optically active forms of carboxycyclopropylglycine.